USPTO Patents Application 09651290

j| United States Patent and Trademark Office

APPLICATION NO.

FILING DATE

FIRST NAMED INVENTOR

UNITED STATES DEPARTMENT OF COMMERCE

United States Patent and Trademark Office

Address: COMMISSIONER OF PATENTS AND TRADEMARKS

Washington, D.C. 2G23I

www.uspto.gov

| ATTORNEY DOCKET NO. | CONFIRMATION NO.

09/651,290

08/30/2000

Marcin S. Filutowicz

7590 07/12/2002

Janet E Reed

Saul Ewing Remick & Saul LLP
Centre Square West
1500 Market St 38th Floor
Philadelphia, PA 19102

P00154US/13238/00016

2591

EXAMINER

FORD, VANESSA L

ART UNIT

PAPER NUMBER

1645

DATE MAILED: 07/12/2002

Please find below and/or attached an Office communication concerning this application or proceeding.

PTO-90C (Rev. 07-01)

Office Action Summary

Application No.

09/651,290

Examiner

Vanessa L. Ford

Applicant(s)

FILUTOWICZ, MARGIN S.

Art Unit
1645

= The MAILING DATb of ^communication appe ars on the cover sheet with the c'orresponuence «uu.«~ -

P TsHORTENED STATUTORY PER.OD FOR REPLY .8 SET TO EXPIRE 3 MONTH(S) FROM

! \ is'specified above the — (35 U S.C. § 133).
earned patent term adjustment. See 37 CFR 1.704(b).

Status

1 )□ Responsive to communication(s) filed on ?7 February 2002 .
2aM This action is FINAL. 2b)Q This action is non-final.

3 D Since this application is in condition for allowance except for fomnal , matters prosecutor . as to the ments
5 closed in accordance with the practice under Ex parte Quayle, 1935 CD. 1 1 , 453 O.G. 3.
Disposition of Claims

4) H Claim(s) i-f ? u 16-27 and 29 is/are pending in the application.

4a) Of the above claim(s) is/are withdrawn from consideration.

5) Q Claim(s) is/are allowed.

6) El Claim(s) 14, 16-17 and 29 is/are rejected.
7® Claim(s) 18-27 is/are objected to.

8) D Claim(s) are subject to restriction and/or election requirement.

Application Papers

9) Q The specification is objected to by the Examiner.

1<d The drawing(s) filed on is/are: a)D accepted or b)D objected to by the

Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1 .85(a).

1 1) D The proposed drawing correction filed on is: a)D approved b)D disapproved by the Examiner.

If approved, corrected drawings are required in reply to this Office action.

12) D The oath or declaration is objected to by the Examiner.

Priority under 35 U.S.C. §§119 and 120

13) D Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 1 19(a)-(d) or (f).

a)D All b)Q Some*c)D None of:

1 □ Certified copies of the priority documents have been received.

2 □ Certified copies of the priority documents have been received in Application No.

Z.| | oeiuncu OU^i^^ w, .w | /

3 □ Copies of the certified copies of the priority documents have been received in this Nat,ona« Stage
aDDlication from the International Bureau (PCT Rule 1 7.2(a))
♦See the attach^ ,

14 ) D Acknowledgment is made of a Cairn for domestic priority under 35 U.S.C. § 1 19(e) (to a provisional application).

a) □ The translation of the foreign language provisional applicafion has been receded

15) D Acknowledgment is made of a claim for domestic pr.or.ty under 35 U.S.C. §§ 120 and/or 121.

Attachment(s)

1) Notice of References Cited (PTO-892)

2) □ Notice of Draftsperson's Patent Drawing Review (PTO-948)

3) □ Information Disclosure Statement(s) (PTO-1449) Paper No(s) .

4) □ Interview Summary (PTO-413) Paper No(s).

5) □ Notice of Informal Patent Application (PTO-152)

6) D Other:

U.S. Patent and Trademark Office

PTO-326 (Rev. 04-01)

Office Action Summary

Part of Paper No. 14

Application/Control Number: 09/651,
Art Unit: 1645

Page 2

DETAILED ACTION

! . This Office Action is responsive to Applicant's response filed February 27, 2002
is acknowledged. Cairns 15 and 30 have been cancelled. Claims 1, 14 and 29 have
been amended.

2. The text of those sections of Title 35. U.S. Code not included in this
action can be found in the prior Office Action.

REJECTIONS WITHDRAWN

3. ,n view of Applicant's amendment the following Rejections have been withdrawn:

a) Rejection of claims 14-15 under 35 U.8.C. 112, second paragraph, pages 6-7,
ffig£$S£lZT^« »«erU.S.C. 102(b), Pa 3 es T- 8 ,
S^SSTS&^S^C. 102(b), pages 9-10, paragraph 5 of
the previous Office action.

CLAIM OBJECTIONS

4 . Claims 18-27 are objected to because they depend from rejected based claims.

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Art Unit: 1645

REJECTIONS MAINTAINED

5. The rejection of claims 1-12, 14, 16-17 and 29 are rejected under 35 U.S.C. 112,
first paragraph is maintained for the reason set forth on pages 2-6 of the previous Office
Action.

The rejection was on the grounds that the specification contained subject matter
which was not described in the in such a way as to enable one skilled in the art to which
it pertains or with which it is most nearly connected, to make and/or use the invention.

The claims are drawn to an antibacterial agent which comprises a non-
pathogenic bacterial cell harboring at least one transmissible plasmid comprising: an
origin of replication wherein the initiation of replication at the origin is negatively
controlled by a plasmid replication repressor, an origin of transfer and optionally, at least
one screenable marker gene and a pharmaceutical preparation comprising the

ant ' ba The^pedfication generically claims an antibacterial agent that comprises a non-
pathogenic donor bacterial cell harboring at least one transmissible plasmid comprising
an origin of replication, an origin of transfer and optionally at least one screenable gene
marker The claimed invention further includes a plurality of microorganisms of which
the donor cell or recipient cell can be obtained. The specification does not provide
substantive evidence that the claimed antibacterial agent can maintain stability or that
the pharmaceutical preparation comprising the antibacterial agent is capable of treating
bacterial infections. This demonstration is required for the skilled artisan to be able to
use the claimed invention for the intended purpose of treating bacterial infections.
Without this demonstration, the skilled artisan would not be able to reasonably predict
whether the claimed invention could survive in vivo use or whether the artisan would be
able to predict if the administration of the claimed pharmaceutical preparation, would be
able to treat bacterial infections. *u,*o rauU oii
There are several factors that contribute to the stability of plasmids that are well
known in the art. These factors include: 1 ) the ability of conjugative transfer within and
between genera, 2) essential components required to ensure stabilization 3) mating pair
stabilization and 4) compatibility between the donor and recipient cell. The abihty to
reasonably predict the capacity of plasmids to be conjugatively transferred within
genera and especially between genera, maintain stability is problematic. This ms
evidenced by Ambrozic et al, Microbiology (ENGLAND), February 1998 1440* 2), p.
343-352) Ambrozic et al teach that conjugal transfer was demonstrated with low
frequency to Klebsiella pneumoniae suggesting that a natural barrier effectively bars
transfer. Specific sequences are also required for the complete stabilization of
plasmids For example, Roberts etal, (Journal of Bacteriology, November 1990, 172
(11) p 6204-6216) teach that one of the regions responsible for stable inheritance of
the broad host range plasmid RK2 is contained within the Pstl C fragments. Robert et

Application/Control Number: 09/651 ,290
Art Unit: 1645

Page 4

al teach that the PSTI C fragment itself is not required for stabilization activity, however
the PSTI C fragment encodes a multimer resolution system which required adjacent
sequence to maintain complete stabilization. Mating stabilization during conjugative
transfer between the donor and recipient cell is also required. Klimke et al, (Journal of
Bacteriology, August 1998, 180 (16), p. 4036-4043) teach that mating stabilization
occurs during conjugative transfer whereby the donor cell and recipient cells form a tight
junction which requires pili as well as TraN and TraG (proteins involved in matting pair
stabilization) in the donor cell. Klimke et al teach that the TraN and not the F pili
appears to interact with OmpA and LPS moieties during conjugation, resulting in mating
stabilization Klimke et al further teach that this is the first step in efficient mobilization
of DNA Compatibility between the donor cell and the recipient cell is also necessary.
This is further evidenced by Rahal et al, (/Anna/es de microbiologie (FRANCE), May-
June 1978 129 (4) p. 409-414). Rahal et al teach that very few multi-resistant strains
of Vibrio cholerae have been isolated this may be due to a high frequency of plasmids
being lost due to the incompatibility of groups. Since genetic mutations are used to
determine the structural and functional properties of the claimed antibacterial agent and
pharmaceutical composition the predictability of which changes or mutations can be
tolerated in the host and still retain similar activity requires a knowledge of and guidance
with regard to which mutations can be made in the plasmid wherein stability will be
maintained The cited references have shown that unpredictability exists regarding
plasmid stability. Therefore, it can be concluded that undue experimentation would be
required to make and use the claimed antibacterial agent without proper guidance.

The specification does not enable any person skilled in the art to which it
pertains or with which it is most nearly connected, to make and use the pharmaceutical
preparation commensurate in scope with these claims. The specification fails to teach
how to make and use the claimed pharmaceutical preparation. The term
"pharmaceutical" encompasses the ability of the specific antigen to induce protective
immunity to a host. The specification does not disclose how to formulate the
pharmaceutical preparation or what dosages are required to treat a patient with a
bacterial infection? The specification further does not disclose whether the
antibacterial agent can be survive the mouth, stomach or intestines without being
degraded or if the antibacterial agent is capable of reach the target organs necessary to
treat a particular bacterial infection. Therefore, it is unclear as to how to formulate a
pharmaceutical preparation comprising the antibacterial agent which will treat anx

bacterial infection. .

Factors to be considered in determining whether undue experimentation is
required are set forth in In re Wands 8 USPQ2d 1400. They include (1) the quantity of
experimentation necessary, (2) the amount of direction or guidance presented, (3) the
presence or absence of working examples, (4) the nature of the invention, (5) the state
of the prior art, (6) the relative skill of those in the art, (7) the predictability or
unpredictability of the art and (8) the breadth of the claims.

Applying the above test to the facts of record, it is determined that 1 ) no
declaration under 37 C.F.R. 1.132 or other relevant evidence has been made of record
establishing the amount of experimentation necessary, 2) insufficient direction or

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Art Unit: 1645

guidance is presented in the specification with respect to selecting a stable antibacterial
aqent and pharmaceutical preparation that would achieve a desire level of success
when administered to a patient with a bacterial infection that is capable of treating that
bacterial infection, 3) there are limited working examples which suggest the desired
results of a antibacterial agent that is to be used in a pharmaceutical preparation to treat
any bacterial infection, 4) the relative skill of those in the art is commonly recognized as
quite high (post - doctoral level), and the lack of predictability in the field to which the
invention pertains is recognized in the art as evidenced by the cited prior art.

In view of all of the above, in view of the lack of predictability in the art, it is
determined that it would require undue experimentation to make and use the claimed
invention.

Applicant urges that the present application teaches antibacterial agents
comprising "killer plasmids" which are conjugatively transferred from a nonpathogenic
donor to a pathogenic recipient and the application teaches that both oh and tra are
required. Applicant urges that the instant disclosure has clearly and precisely pointed
out the limitations of what he regards as his invention. Applicant urges that the
Examiner is reading into the claims a limitation that is not contained within the invention.
Applicant urges that he considers the stability of the plasmid in neither the donor nor the
recipient to be critical to the operation of the invention as claimed and that the more
important parameter is that the bacteria are capable of conjugatively transferring the
plasmid to a recipient cell. Applicant urges that there is no limitation within the claimed
in invention regarding in vivo survival or use. Applicant urges that Ambozic et al
supports the proposition that a "natural barrier " effectively bars transfer of a plasmid by
conjugal transfer to Klebsiella pnuemoniae. Applicant also urges that the claimed
invention differs because it teaches wide host range plasmids and that Ambozic et al
only teach the use of narrow host range plasmids (i.e. ColV). Applicant urges that any
toxic or killing effect of the plasmid would not be present until after the successful

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Art Unit: 1645

conjugative transfer to the recipient and that Klebsiella is not specifically claimed.
Applicant urges that Roberts et al support the position that specific sequences are
required for complete stabilization of plasmids. Applicant urges that without complete
stabilization a loss of even 10 to 12% would not render the invention inoperable or
unable to be practiced. Applicant urges that Klimke et al teach that mating stabilization
during conjugative transfer between donor and recipient cell is required. Applicant
urges that in order to practice the claimed invention transfer genes would have to be
present. Applicant urges that Rahal et al disclose that compatibility between donor cell
and the recipient cell is necessary. Applicant urges that the finding disclosed by Rahal
et al do not preclude one from practicing the claimed invention.

Applicant's arguments filed February 27, 2002 have been fully considered but
they are not persuasive. The claims are drawn to an antibacterial agent which
comprises a non-pathogenic bacterial cell harboring at least one transmissible plasmid
comprising: an origin of replication, an origin of transfer and optionally, at least one
screenable marker gene wherein the donor cell further comprises one or more transfer
genes conferring upon the donor cell the ability to conjugatively transfer the
transmissible plasmid to the recipient cell and wherein the donor cell produces the
plasmid replication repressor and further wherein at least one recipient cell is a
pathogenic bacterium that does not produce the plasmid replication repressor, thereby
enabling the transmissible plasmid to undergo runaway replication in the recipient cell.
Despite the knowledge in the art for using antibacterial agents, the specification fails to
specifically point out how to make and use the claimed invention. Applicant asserts that

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Art Unit: 1645

the Examiner is reading limitations that are not included in the claimed invention. The
Examiner points out that the Applicant must provide in the instant specification
information so that one skilled in the art could make and use the claimed invention. The
specification fails to provide guidance regarding whether the experiments disclosed on
pages 17-18 were done in vivo or in vitro? The specification discloses in Example 2 a
mutated pir gene. Which mutation was used in Example 2? What mutations can be
made in the antibacterial agent and the pharmaceutical composition can maintain its
antibacterial activity? What pathogenic bacterial cells were killed? How would one
monitor the killing of pathogenic cells in vitro? The specification states that
"pharmaceutical preparations comprising the donor bacteria are formulated in dosage
unit from for ease of administration and uniformity". The specification states "that the
dosage unit form refers to a physically discrete unit of the pharmaceutical preparation
appropriate for the undergoing of treatment" (page 1 6). Where patients treated with the
pharmaceutical composition? What bacterial diseases where treated? Can any
bacterial infection or disease be treated using the pharmaceutical composition? What
concentration of the pharmaceutical composition is sufficient to treat a bacterial
infection? Was the pharmaceutical composition able to reach the site of infection? The
metes and bounds of the claimed invention cannot be ascertained by the information
disclosed in the specification. Therefore, one of skill in the art would require guidance,
in order to make and use the claimed invention. Without proper guidance, the
experimentation is undue.

Application/Control Number: 09/651 ,290 Pa 9 e 8

Art Unit: 1645

Applicant urges that Ambozic et al supports the proposition that a "natural barrier
" effectively bars transfer of a plasmid by conjugal transfer to Klebsiella pnuemoniae
and that the claimed invention differs because the claimed invention teaches wide host
range plasmids and Ambozic et al teach the narrow host range plasmids (i.e. ColV).
Applicant's claimed invention is drawn to an antibacterial agent which comprises a non-
pathogenic bacterial cell harboring at least one transmissible plasmid comprising: an
origin of replication, an origin of transfer and optionally, at least one screenable marker
gene wherein the donor cell further comprises one or more transfer genes conferring
upon the donor cell the ability to conjugatively transfer the transmissible plasmid to the
recipient cell wherein the result is runaway replication in the recipient cell. The claimed
invention encompasses bacteria of the genera Klebsiella. The ability to reasonably
predict the capacity of plasmids to be conjugatively transferred within genera and
especially between genera, maintain stability is problematic. This is evidenced by
Ambrozic et al. Ambrozic et al teach that conjugal transfer was demonstrated with low
frequency to Klebsiella pneumoniae suggesting that a natural barrier effectively bars
transfer. Applicant urges that any toxic or killing effect of the plasmid would not be
present until after the successful conjugative transfer to the recipient and that Klebsiella
is not specifically claimed. The claimed invention requires the transfer of a
"transmissible plasmid" from a donor cell to a recipient cell. A toxic or killing effect
cannot occur if the transmissible plasmid" is not conjugatively transferred from the donor
cell to the recipient cell. Therefore, in view of the teaching of Ambrozic et al one can

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Art Unit: 1645

reasonably assume that the capacity of plasmids to be conjugatively transferred within
and between aH genera of bacteria is unpredictable.

Applicant urges that Roberts et al support the position that specific sequences
are required for complete stabilization of plasmids. Applicant urges that without
complete stabilization a loss of even 10 to 12% would not render he invention
inoperable or unable to be practiced. Roberts et al teach that one of the most important
survival characteristics of naturally occurring plasmids the ability to ensure that both
progeny of a cell division contain at least one copy of the plasmid and this often
accomplished in spite of a very low number of plasmid copies per cell. Roberts et al
teach that the replication control mechanism to ensure a constant number of plasmid
copies per chromosome which provides a pool of plasmids for segregation to each
daughter cell is crucial . Therefore, one skill in the art can reasonable assume that
stabilization is necessary for conjugative transfer of a "transmissible plasmid" from a
donor cell to a recipient cell wherein the result is runaway replication in the recipient
cell.

Applicant urges that Klimke et al teach that mating stabilization during
conjugative transfer between donor and recipient cell is required and that transfer genes
would have to be present to practice the claimed invention. Since the claimed invention
is directed to any bacterial donor and any recipient cell, the Klimke et al reference was
cited to point out that mating stabilization during conjugative transfer between donor and
recipient cell is required.

Page 10

Application/Control Number: 09/651,290
Art Unit: 1645

Applicant urges that Rahal et al disclose that compatibility between donor cell
and the recipient cell is necessary. Applicant urges that the finding disclosed by Rahal
et al do not preclude one from practicing the claimed invention. Rahal et al teach that
very few mufti-resistant strains of Vibrio cholera* have been isolated this may be due to
a high frequency of plasmids being lost due to the incompatibilrty of groups. Since
genetic mutations are used to determine the structural and functional properties of the
claimed antibacterial agent and pharmaceutical compositon the predictability of which
changes or mutations can be tolerated in the host and still retain similar activity requires
a knowledge of and guidance with regard to which mutations can be made in the
plasmid wherein stability will be maintained. The cited references have shown that
unpredictability exists regarding plasmid stability. Therefore, it can be concluded that
undue experimentation would be required to make and use the claimed antibacterial

agent without proper guidance.

The specification has also failed to provide guidance regarding how to use the
pharmaceutical composition comprising the antibacterial agent. The specification does
not specifically disclose whether the experiments disclose in Examples 1 and 2 were
performed in vivo or in vitro, if ajl bacterial infections or diseases can be treated, if any
concentration of the pharmaceutical is sufficient to treat a bacterial infection, if all
mutations can be made in the antibacterial agent and the pharmaceutical composition is
able to retain its antibacterial ability or if all pharmaceutical composition formulations are
able to reach the site of infection? The metes and bounds of the claimed invention
cannot be ascertained by the information disclosed in the specification. Therefore, in

Page 1 1

Application/Control Number: 09/651,290
Art Unit: 1645

view of the teaching of the cited prior art. one of skill in the art would require guidance,
in order to use the claimed invention. Without proper guidance, experimentation is

undue.

6 . Applicants amendment necessitated the new ground(s) of rejection presented in
this Office action. Accordingly, THIS ACTION IS MADE FINAL. SeeMPEP

§ 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37

CFR 1.136(a).

A shortened statutory period for reply to this final action is set to expire THREE
MONTHS from the mailing date of this action. In the event a first reply is filed within
TWO MONTHS of the mailing date of this final action and the advisory action is not
mailed until after the end of the THREE-MONTH shortened statutory period, then the
shortened statutory period will expire on the date the advisory action is mailed, and any
extension fee pursuant to 37 CFR 1 .1 36(a) will be calculated from the mailing date of
the advisory action. In no event, however, will the statutory period for reply expire later
than SIX MONTHS from the date of this final action.

Paqe 12

Application/Control Number: 09/651 ,290
Art Unit: 1645

7. Any inquiry of the general nature or relating to the status of this general
application should be directed to the Group receptionist whose telephone number is
(703) 308-0196.

Papers relating to this application may be submitted to Technology Center 1600,
Group 164^by fSile transmission. The faxing of such papers must conforrr .with
The notice published in the Office Gazette, 1096 OG 30 {^^^^^
applicant wish to FAX a response, the current FAX number for the Group 1600 is (703)

308-4242.

Any inquiry concerning this communication from the examiner should be directed
to Vanessa L Ford whose telephone number is (703) 308-4735. The examiner can
nolany Te reached on Monda? - Friday from 7:30 AM to 4:00 PM. If
the examiner by telephone are unsuccessful, the examiner's supervisor, Lynette Sm.th,
can be reached at (703) 308-3909.

W

Vanessa L. Ford
Biotechnology Patent Examiner
June 3, 2002

s^RK NAVARRO